Signaling of short-term and long-term regulation of intestinal epithelial type 1 Na+/H+ exchanger by interferon-gamma

• Type: Article in International Scientific Journal
• Date: 2005

Authors

Magro F (Author) FMUP; Sonia Fraga (Author) Other; soares-da-silva, p (Author) FMUP

Journal

Title: British Journal of Pharmacology

Vol. 145

Pages: 93-103

ISSN: 0007-1188

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 17 Citations

Scopus - 20 Citations

Other information

Authenticus ID: P-000-3FK

DOI: 10.1038/sj.bjp.0706167

Abstract (EN): 1 The present study evaluated the effect of interferon-γ (IFN-γ) on intestinal Na+/H+ exchange (NHE) activity and the intracellular signaling pathways set into motion after IFN-γ receptor activation. 2 Caco-2 cells express endogenous NHE1, NHE2 and NHE3 proteins, as detected by immunoblotting. Short- (0.5 h) and long- (24 h) term exposure of Caco-2 cells to IFN-γ resulted in a concentration-dependent decrease in NHE activity. Inhibition of NHE activity by IFN-γ was absent in cariporide-treated cells, but not in cells treated with S-3226. The long- term exposure to IFN-γ was accompanied by a 20% increase in surface NHE1 abundance and no changes in total NHE1 abundance. 3 Inhibition of Raf1, mitogen-activated protein kinase kinase (MAPKK/MEK) and p38 MAPK with, respectively, GW 5074, PD 98059 and SB 203580 and downregulation of protein kinase C (PKC) with phorbol-12,13-dibutyrate (100 nM for 24 h) prevented inhibition of NHE activity by IFN-γ (0.5 and 24 h exposure). The signal transducer and activator transcription factor 1 (STAT1) inhibitor epigallocatechin-3-gallate ( EGCG) prevented inhibition of NHE activity by long- but not the short-term treatment with IFN-γ. 4 Treatment with IFN-γ activated phospho-p38 MAPK, this effect being detected as early as 1 h, persisting over 3 h and decreasing after 24 h. IFN-γ produced a sustained action of phospho-STAT1 that was prevented by EGCG and partially attenuated by SB 203580 and insensitive to downregulation of PKC. 5 In conclusion, short- and long-term inhibition of NHE1 activity by IFN-γ involves a complex signaling pathway that includes PKC activation and STAT1 phosphorylation, respectively, but is not accompanied by downregulation of NHE1.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11